NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF.
NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF.
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DOI：
10.1016/j.ebiom.2017.01.013
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Smith AG
中科院分区：
文献类型：
--
作者：
Fane ME;Chhabra Y;Hollingsworth DEJ;Simmons JL;Spoerri L;Oh TG;Chauhan J;Chin T;Harris L;Harvey TJ;Muscat GEO;Goding CR;Sturm RA;Haass NK;Boyle GM;Piper M;Smith AG
虽然肿瘤细胞的侵袭和转移是导致癌症相关死亡的主要因素，但控制该过程的机制仍然不清楚。此外，已知肿瘤细胞亚群的表型差异支持与肿瘤进展相关的替代行为，如增殖、存活和侵袭。在黑色素瘤的背景下，两种转录因子BRN 2和MITF之间的异质性分别与主要侵袭性和增殖性行为之间的表型转换相关。表观遗传变化，响应于外部线索，已被提出来支持这一过程，但表型转换发生的机制尚不清楚。在这里，我们报告的NFIB转录因子作为一种新的下游效应的BRN 2功能在黑色素瘤细胞的迁移和侵袭性的特点，这些细胞的鉴定。此外，NFIB的功能似乎通过经由多梳组蛋白EZH 2的上调实现的表观遗传机制来驱动侵袭性表型。NFIB介导的EZH 2上调的一个值得注意的靶点是降低的MITF表达，这进一步促进了增殖性更低、侵袭性更强的表型。总之，我们的数据表明，NFIB有能力促进黑色素瘤细胞染色质状态的动态变化，以促进迁移，侵袭和转移。NFIB介导BRN 2下游的慢循环、高度侵袭性/迁移性黑素瘤细胞表型。NFIB增加BRN 2下游的EZH 2表达，这进一步降低MITF水平。NFIB表达由侵袭性基因签名定义，并与原发性和转移性人黑素瘤肿瘤中的BRN 2共定位。黑色素瘤是一种异质性癌症，由许多细胞群组成，这些细胞群诱导肿瘤生长或侵入全身（转移）的能力不同。已经发现这些人群来回切换以驱动入侵和进展。这个过程似乎是由两个基因MITF和BRN 2之间的逆轴控制的。BRN 2驱动转移性扩散，但其作用过程尚未得到很好的表征，无法在临床上靶向。这项研究揭示了基因NFIB在驱动BRN 2下游侵袭中的作用。重要的是，它似乎通过EZH 2驱动这一过程，EZH 2可以在治疗上靶向减少转移。
While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis. NFIB mediates a slow cycling, highly invasive/migratory melanoma cell phenotype downstream of BRN2. NFIB increases EZH2 expression downstream of BRN2, which further decreases MITF levels. NFIB expression is defined by an invasive gene signature and colocalises with BRN2 in primary and metastatic human melanoma tumours. Melanoma is a heterogeneous cancer, made up of many cellular populations that differ in their ability to induce tumour growth or invasion throughout the body (metastasis). These populations have been found to switch back and forth to drive invasion and progression. This process appears to be controlled by an inverse axis between two genes, MITF and BRN2. BRN2 drives metastatic spread, but the process by which it acts is not well characterized and cannot be targeted clinically. This study has uncovered a role for the gene NFIB in driving invasion downstream of BRN2. Importantly, it appears to drive this process through EZH2, which can be targeted therapeutically to reduce metastasis.